Prenatal Exome Sequencing of Fetuses with Central Nervous System Anomalies Based on Prenatal Ultrasound and Magnetic Resonance Imaging Diagnosis — A Retrospective Cohort Study and System Review

Prenatal Exome Sequencing of Fetuses with Central Nervous System Anomalies Based on Prenatal Ultrasound and Magnetic Resonance Imaging Diagnosis — A Retrospective Cohort Study and System Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prenatal Exome Sequencing of Fetuses with Central Nervous System Anomalies Based on Prenatal Ultrasound and Magnetic Resonance Imaging Diagnosis — A Retrospective Cohort Study and System Review Miss Jia Yao, Yan Wang, DR. Gang Li, Zhitao Zhang, Yuan Lv, Lizhu Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5459992/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Assessing the incremental yield of prenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) in the diagnosis of central nervous system (CNS) anomalies based on prenatal ultrasound and magnetic resonance imaging (MRI) diagnoses. Methods In this retrospective cohort study, we collected the ES results of fetuses diagnosed with CNS anomalies through prenatal ultrasound and MRI between 2019 and 2023, who also had negative CMA results. We performed subgroup analyses to assess detection rates for different phenotypes in order to identify associated genes and variants. A meta-analysis combining our study with relevant research was performed to further explore the association between phenotype and ES. Results In the cohort study of 219 cases, ES identified pathogenic/likely pathogenic single nucleotide variations in 36 cases (16%). The highest detection rate was observed in cases with multisystem malformations (25%, 14/55), followed by multiple CNS anomalies (15%, 2/13) and isolated CNS anomaly (13%, 20/151). The most commonly identified isolated CNS anomaly was agenesis of the corpus callosum (31%, 5/16). Neural tube defects with urogenital anomalies were strongly linked to positive ES results (57%, 4/7). The meta-analysis of 989 cases from 22 studies showed a pooled ES diagnostic yield of 27% [(95% (CI), 21–34%)]. The highest detection rates were in cases of corpus callosum anomalies with facial abnormalities (75%, 8/11) and neural tube defects with urogenital malformations (80%, 12/15). The detection rate for three or more types of complex central nervous system (CNS) abnormalities was 43% (95% confidence interval, 31%-58%), which was significantly higher than that for only two abnormalities, which was 10% [(95% (CI), 4%-18%). No significant difference in diagnostic yield was found between cases identified by prenatal MRI combined with ultrasound [27% (95% confidence interval, 20–36%)] and those identified by ultrasound alone [25% (95% confidence interval, 17–35%)]. Conclusions ES provided a significantly higher diagnostic yield than CMA for fetuses with CNS abnormalities. Additionally, diagnostic rates for variants varied across different phenotypic abnormalities. Central nervous system anomalies Exome sequencing Prenatal diagnosis Fetus Figures Figure 1 Figure 2 Figure 3 Introduction Central nervous system (CNS) abnormalities, constituting 9% of fetal malformations, significantly impact perinatal death, potentially affecting quality of life depending on severity. (1) Prenatal imaging (ultrasound and magnetic resonance imaging [MRI]) identifies various CNS abnormalities. (2–4) However, genomic variations are often overlooked; therefore, in many cases, relying solely on imaging diagnosis is incomplete. Karyotyping and chromosomal microarray analysis (CMA) are routine invasive prenatal diagnostic methods that detect aneuploidy and pathogenic copy number variants (CNVs), (5–8) with a diagnostic rate of approximately 6.2–10.4% for CNS abnormalities. (9–11) Exome sequencing (ES), a next-generation technique, analyzes single nucleotide variants (SNVs) insertions and deletions and gene-coding regions to identify gene-level malformations. (12, 13) Compared to CMA, ES provides a 5–66% increase in overall prenatal abnormalities, (14–22) as a result, ES is increasingly used for fetuses with structural abnormalities and normal CMA results. However, detection rates varied significantly across different studies, potentially due to small sample sizes and a lack of diagnostic yield for various phenotypes. This study was undertaken to detect the incremental yield of ES over negative CMA through a cohort study and meta-analysis of fetal CNS malformations. Furthermore, we sought to evaluate the value of ES in various CNS anomaly phenotypes. Methods Cohort Study This retrospective study, conducted from July 2020 to September 2023, focused on fetal CNS anomalies identified through prenatal ultrasound and MRI at Shengjing Hospital, a tertiary referral center for fetal anomalies affiliated with China Medical University. ES was recommended when CMA tests were non-diagnostic. Genetic counseling was provided to pregnant women and their families, explaining the necessity, limitations, and residual risks of genetic testing. After informed consent was obtained, genomic DNA was extracted from amniotic cells using the QIAGEN DNA Midi/Mini Kit according to the manufacturer's protocol. This study was approved by the Hospital Ethics Committee of Shengjing Hospital, China Medical University. Sequencing involving 219 cases was performed using a NovaSeq 6000 sequencer (Illumina, San Diego, CA, USA) with 150-bp paired-end reads. The entire bioinformatics pipeline, from FASTQ files to the final report, was constructed using the GeneX Genetic Analysis Platform (Basecare Medical Co., Ltd.). FASTQ files were aligned against the hg19/GRCh37 reference genome using BWA v.0.7.17. (23) Variant calling for SNVs and indels was performed using Genome Analysis Toolkit v.4.1.8.0. (24) Alongside SNVs and small indels, the GeneX pipeline detects CNVs using base CNVs proprietary CNVs-caller, which utilizes coverage information and is expected to detect CNVs with a resolution of two exons in the heterozygous state and a single exon in the homozygous state. (25) The analysis required a minimum average coverage of 100 × for sample inclusion. The family-case analysis considered various inheritance modes. The filtering process retained rare variants with minor allele frequency <10%, protein-altering variants, variants in coding regions or within 20 bp from splice junctions, and variants with high or medium aggregated quality scores. GeneX prioritized variants based on pathogenicity and clinical information, transcribed into Human Phenotype Ontology (HPO) terms (https://hpo.jax.org/app/). Sequencing data analysis was performed using the Verita Trekker ® Mutation Site Detection System and GATK (https://software.broadinstitute.org/gatk/). Variant annotation databases comprised population databases, prediction algorithms, and disease/phenotype databases, including OMIM (http://www.omim.org), ClinVar (http://www.ncbi.nlm.nih.gov/clinvar), HGMD (http://www.hgmd.org), and HPO. The report interpretation followed the American College of Medical Genetics and Genomics (ACMG) guidelines, categorizing mutations into pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), possibly benign, and benign. (26) Only P or LP diagnostic variants were included in the positive diagnostic group. Data reanalysis was performed upon the emergence of a new phenotype during the third trimester or postpartum follow-up. Newly discovered diagnostic variants were validated through Sanger sequencing. Meta-analysis Protocol and Registration The study protocol has been prospectively registered in PROSPERO (CRD42023387481). The meta-analysis followed the PRISMA guidelines. (27) (Table S1, S2) Data Sources From January 2010 to December 2023, we electronically searched databases (Medline, Embase, Web of Science, and Cochrane) using a comprehensive strategy with relevant Medical Subject Headings terms and keywords, including ("Prenatal Diagnosis" OR "Fetal Diseases" OR "Fetal Development" OR "Congenital Abnormalities") AND ("Whole Genome Sequencing" OR "Whole Exome Sequencing" OR “Exome sequencing” OR "DNA Sequence Analysis"). Additional file 4outlines the detailed search strategy. The reference lists of pertinent articles were reviewed manually, and experts in prenatal genomics were consulted to discover additional relevant studies. Eligibility Criteria and Study Selection Eligibility criteria for observational studies included studies involving more than three fetuses with CNS abnormalities, presenting clear fetal phenotypes, including variants classified as LP/P, causative of the fetal phenotype, and having non-diagnostic CMA results. Any missing information prompted email inquiries to the corresponding authors. Exclusions comprised case reports, opinion articles, or letters; studies lacking detailed phenotypes; studies utilizing gene panels; and studies with unextractable data after a request for additional information from corresponding authors. Two independent reviewers (Y. J. and W. Y.) evaluated the abstracts of pertinent studies, and full-text articles underwent review once the met the inclusion criteria. A third investigator (C. L. Z.) independently resolved any disagreements between the reviewers. Data Collection Two reviewers independently extracted data capturing study characteristics and outcomes. The extracted data encompassed the study site, publication timeline, inclusion criteria, detection methods, sample size, count of positive case, fetal anomalies, implicated genes, and associated syndromes or diseases. Quality Assessment Quality of the study was assessed using the Standards for Reporting of Diagnostic Accuracy Studies (STARD) (28) with modifications. Key quality criteria included participants with non-diagnostic CMA results, Sanger sequencing, variants classified according to ACMG or other guidelines, a clear description of both positive and negative fetal phenotypes, and clearly defined inclusion criteria. Data Synthesis and Statistical Analysis Cases were divided into three groups based on CNS abnormalities and extra-CNS abnormalities, as follows: isolated CNS abnormality (one CNS abnormality), multiple CNS abnormalities (two or more CNS abnormalities), and multisystem anomalies (CNS combined with other system abnormalities). Further division into the following six subgroups was based on HPO categories: midline malformations (aplasia of the corpus callosum, holoprosencephaly), anomaly of posterior cranial fossa (Dandy–Walker malformation, cerebellar dysplasia), neural tube defects (NTDs), ventriculomegaly, microcephaly, and intracerebral hemorrhage. Extracted results were pooled for meta-analysis, and ES diagnostic yield was calculated through single-scale analysis. (29) The Clopper–Pearson exact method of a random- (I 2 ≥50) or fixed- (I 2 < 50) effect model was employed, (30) using tau2, χ2, and I 2 statistics to evaluate between-study heterogeneity/variability. Results were assessed through forest plots. Publication bias was assessed using funnel plots, (31-33) quantified using the Egger method (a weighted linear regression of the effect to its standard error) (34) , and adjusted for selection bias using the Copas model. (35, 36) Statistical analyses were performed with STATA 16. (https://www.stata.com/). Two reviewers (Y.J. and W.Y.) independently measured the risk of bias. Results Cohort Study Cohort Characteristics A cohort of 219 cases of fetal CNS abnormalities were collected whose CMA were nondiagnostic. The median gestational age was 25 (12-37) weeks and the median age of pregnant women was 31 (22-41) years. The median turnaround time (TAT) for ES was 21 days. ES Detection Rate P/LP sequence variants were detected in 16% (36/219) cases. The highest detection rate was observed in multisystem malformation (26%, 14/55), followed by multiple CNS anomalies (15%, 2/13) and isolated CNS anomaly (13%, 20/151). Detailed information on the 36 cases with positive ES results is presented in Table 1. In isolated CNS malformations, positive results mainly occurred in agenesis of the corpus callosum (29%, 5/18), while choroid plexus cysts were associated with negative results (0%, 0/3), although the sample size was limited. Table 2 shows the findings of the diagnostic yield based on the category of CNS abnormalities. In addition, five cases of VUS were identified. Associated Extra-CNS Abnormalities Although skeletal abnormalities (49%) were the most common associated abnormalities, cases with urogenital (50%) and cardiovascular (33%) abnormalities showed significantly higher detection rates. In particular, NTD s combined with urogenital anomalies were significantly associated with positive ES results (57%, 4/7). Genetic Characteristics Among the diagnosed variants, 44% exhibited an autosomal recessive (AR) inheritance pattern, 40% exhibited an autosomal dominant (AD) inheritance pattern, 11% exhibited an X-linked recessive (XLR) inheritance pattern and 5% exhibited an X-linked dominant (XLD) inheritance pattern. Among the positive cases, 65% were inherited mutations and 35% were de novo mutations. Furthermore, seven new variation sites were identified in six genes) (PDHA1, TMEM231, CPLANE1, CC2D2A, TREX1, CEP135). The most common syndromes in positive cases were Meckel syndrome (3/36, 8%), Congenital Microcephaly (2/36, 6%) and Aicardi-Goutieres syndrome (2/36, 6%), with the remaining cases occurring once each (n=29). Pregnancy Outcome The most common pregnancy outcome was termination of pregnancy (83.1%, n = 182/219). Patients whose fetuses had a P/LP mutation (83.3%, 30/36) were more likely to terminate than those with undiagnostic results (83.1%, 152/183); however, the difference was not statistically significant (P = 0.83). Meta-analysis Study Selection and Characteristics A total of 1879 records were identified in the database search. After screening the abstract, 113 articles were assessed, of which 21 met the inclusion criteria (18-22, 37-52) along with our cohort study. Twenty-two studies (989 cases) were included in the meta-analysis (Figure 1), among which 9 were prospective and 13 were retrospective. Seventeen series used Trio-ES, and five employed proband-ES and Trio-ES. Average gestational and maternal ages were 21 (12–37) weeks and 31 (22–41) years, respectively. The median TAT was 22 (4–56) days. The most common pregnancy outcome with positive results was termination of pregnancy (86.0%, 135/157). Study characteristics are detailed in Additional file 2. Figure 2 presents the overall quality assessment using modified STARD criteria. Synthesis of R esults and R isk of B ias In total, 238 cases were identified of P or LP variants. The detection rates of general meta-analysis were: (1) the overall CNS anomaly: 27% [95% confidence interval (CI), 21-34%]; (2) Isolated CNS anomaly: 16% [95% (CI), 10-22%]; (3) Multiple CNS anomalies: 26% [95% (CI), 10-44%]; (4) multisystem anomalies: 35% [95% (CI), 29-41%] (Figure 3.). The pooled diagnostic yield of specific abnormal phenotypes is presented in detail in Table 3. In cases of complex CNS abnormalities, the positive diagnostic rate for fetuses with three or more CNS anomalies [43% (95% confidence interval, 31-58%)] differed significantly from that for those with two CNS anomalies [10% (95% confidence interval, 4-18%)]. Isolated NTDs are closely related to the negative results of ES, with a detection rate of 0% [95% (CI), 0-5%]. Of the 53 cases of isolated NTDs, only one case from our cohort study identified a pathogenic de novo SNV. The pooled detection rate of VUS was 5% [95% (CI), 1-11%]. The diagnostic yield for CNS abnormalities identified by prenatal MRI combined with ultrasound and by ultrasound alone showed no statistical difference [27% (95% confidence interval, 20-36%)] vs [25% (95% confidence interval, 17-35%)]. Genetic Characteristics Among the 238 cases with a positive molecular ES diagnosis, 246 variants from 137 genes were identified, with 46 occurring more than once. The frequently affected genes were L1CAM (n=10), TUBA1A (n=10) and CHD7 (n=8). Inherited mutations (58%) were the most common origin of pathogenic genes, with AD inheritance presenting the highest proportion (46%). The predominant syndromes detected were Meckel–Gruber syndrome (n=15) and lissencephaly (n=13) (Additional file 3). Associated Extra-CNS Abnormalities Skeletal abnormalities were the most prevalent association with CNS anomalies (45%). Among positive cases, CNS anomalies combined with NT thickening (56%), urogenital abnormalities (56%), and eyes abnormalities (55%) presented the highest diagnostic rate. Among the different phenotypes, corpus callosum anomalies combined with facial abnormalities (73%) and NTDs combined with urogenital malformations (80%) showed the highest detection rate. No significant difference was found between the diagnostic rate of CNS anomalies combined with one extra-CNS system abnormality [29% (95% confidence interval, 20-39%)] and that of CNS anomalies combined with two or more system abnormalities [45% (95% confidence interval, 32-58%)]. Discussion Principal Findings Our cohort study and meta-analysis underscore the significant additional diagnostic yield of ES over CMA, suggesting its high efficacy in detecting prenatal CNS anomalies. Results in the Context of What is Known As Tolusso et al. (18) reported, ES played a vital role in assessing recurrence risk and guiding perinatal care. The results of our study suggested that ES had little effect on the current pregnancy outcome, but it had important guiding significance for the next pregnancy. Over half of the diagnosed cases in our study carried a significant recurrence risk, providing valuable information for future reproductive options, including prenatal diagnosis or preimplantation genetic testing. By identifying potential pathogenic mutations, exome sequencing can help parents understand genetic risks and make more informed decisions in future pregnancies. In addition, the gradual decrease in the TAT of ES (the average TAT reported in 2014 was 18 weeks, (53) and the average TAT in the meta-analysis was 22 days) may increase the practicality of ES in prenatal genetic testing. ES suitability as the primary prenatal genetic test for CNS abnormalities remains debated owing to its advantages and limitations. Tan et al. (20) suggested using ES after obtaining negative CMA and karyotyping results. However, Yaron et al. (19) recommended ES as the first-level prenatal diagnosis for major CNS abnormalities, as it provided a high diagnostic yield (>50%) . Our results suggest that the use of ES should be prioritized in cases of three or more CNS abnormalities, or the coexistence of CNS malformations with other system malformations. Moreover, a cost assessment of ES is required to demonstrate its clinical cost-effectiveness. Diagnostic yields varied among different phenotypes, with ES presenting a low incremental diagnostic yield for isolated NTDs in our meta-analysis. The etiology of NTDs is multifactorial, involving both environmental factors and various genetic and non-genetic factors. Therefore, in families with a history of recurrent neural tube defects, it is more appropriate to detect genes currently known to be associated with NTDs in order to better understand these potential genetic risks. The diagnostic yield of ES for multisystem abnormalities is related to the category of abnormalities, but there appears to be no significant difference based on the number of abnormalities. When CNS abnormalities are combined with urogenital abnormalities, eyes abnormalities, cardiovascular system anomalies, or increased NT, the diagnostic yield is higher. In cases of complex CNS abnormalities, our study suggests that the presence of more than three types of CNS abnormalities in a fetus is often indicative of a higher likelihood of SNVs. Owing to the differences in phenotypic diagnostic yields, accurate and comprehensive descriptions of abnormal phenotypes are important for genetic diagnosis. Phenotype-driven approaches can significantly improve molecular diagnosis and clinical consultation. (54) Standardizing the recording of phenotypes and expanding terms for prenatal discovery of HPO are essential, as they can enhance the elucidation of the relationship between phenotype and prognosis through ES. In our cohort study, we identified five cases (2%) with a VUS holding potential clinical relevance. The meta-analysis revealed a 5% increase in VUS yield, which may pose challenges to pregnancy decision-making. A recent cohort study by Shi et al. (55) demonstrated that 78% (108/139) of fetuses with VUS did not exhibit disease features post-birth. Most VUS were determined to be benign, presenting a low risk for adverse disease outcomes. Although most VUS may prove benign or unrelated, a small number will eventually emerge as P/LP owing to data-sharing tool update (Franklin Users Community (56) ). Future C linical and R esearch I mplications In cases where three or more CNS abnormalities are present, or where CNS malformations coexist with abnormalities in other systems, ES should be considered the preferred option. The future clinical and research significance is to improve our understanding of phenotypic-genotypic relationships. For VUS variants, long-term postnatal follow-ups, postmortem fetal structure investigations, and genetic function studies can provide valuable information for clinical diagnosis and parental decision-making. Further research may also focus on the patient experience of undergoing ES during pregnancy, its impact on clinical diagnosis and parental decision-making processes. Strengths and Limitations There are several strengths to this study. Firstly, it encompassed exome sequencing of maternal-paternal-fetal trios, which aided in the determination of the pathogenicity of identified variants and the assessment of inheritance. All variants were reviewed by a multidisciplinary committee, enhancing the accuracy of variant interpretation. Moreover, all positive results were confirmed using Sanger sequencing in laboratories accredited by the revised standards for clinical laboratories. The studies included in the meta-analysis exhibited high quality, with most studies employing the ACMG classification for genetic variant interpretation and Sanger sequencing for validation. To minimize bias, we included studies with more than three cases in the meta-analysis. This study had some limitations. The relatively limited number of cases restricts the generalizability of conclusions regarding specific phenotype detection rates. Secondly, the review was comprehensive; however, despite employing a random-effects model, high heterogeneity persisted, with subgroup analysis indicating that this was mainly due to the diversity of phenotypes. Thirdly, certain disease processes might exhibit abnormalities later in pregnancy or the early neonatal period, and not all studies provided confirmed postpartum or post-mortem results, potentially leading to neglect of phenotypes and inaccuracies in classification within our review. Lastly, termination of pregnancy was chosen in 80% of cases, preventing further follow-up to investigate the prenatal and postnatal clinical effects of genetic testing benefits. Conclusions Accurate detection of CNS abnormalities is crucial for informed clinical decisions, given their profound impact on the development and quality of life of children. Combined with our cohort study, we systematically reviewed and analyzed the existing literature on ES for prenatal CNS abnormalities. The findings indicate that ES exhibited a high detection rate surpassing other fetal genetic assessment methods. Furthermore, the detection rates for different phenotypes are conducive to clinical consultation. ES is more effective and valuable for detecting genetic diseases than other clinical genetic testing methods, such as CMA. Our research provides a valuable tool for counseling and decision-making regarding reproductive options. Abbreviations CNS Central nervous system MRI Magnetic resonance imaging CMA Chromosomal microarray analysis CNVs Copy number variants ES Exome sequencing SNVs Single nucleotide variants HPO Human Phenotype Ontology ACMG American College of Medical Genetics and Genomics P Pathogenic LP Likely pathogenic VUS Variant of uncertain significance STARD Standards for Reporting of Diagnostic Accuracy Studies NTDs Neural tube defects TAT Turnaround time AR Autosomal recessive AD Autosomal dominant XLR X-linked recessive XLD X-linked dominant CI confidence interval Declarations Ethics approval and consent to participate All individuals participating in this study provided informed consent. The study was approved by the Research Ethics Committee of Shengjing Hospital, China Medical University (Ethical approval number: 2019PS493K). Consent for publication Not Applicable. Data Availability The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Competing interests The authors declare no competing interests Funding This study was supported by the National Natural Science Foundation of China (NO.82272022), National Key Research and Development Program (2021YFC2701003), Young and middle-aged scientific and technological innovation talents in Shenyang (No. RC220070). Corresponding authors had full access to all the data in the study and final responsibility for the decision to submit for publication. Author contributions Jia Yao: Software, Methodology, Formal analysis, Data curation, Investigation, Writing Original Draft Yan Wang: Data curation, Formal analysis, Validation Gang Li: Investigation, Supervision Zhitao Zhang: Case collection *Yuan Lv: Conceptualization, Supervision, Writing-Review & Editing *Lizhu Chen: Conceptualization, Methodology, Supervision, Writing-Review & Editing Acknowledgements We thank the National Natural Science Foundation of China (NO.82272022), National Key Research and Development Program (2021YFC2701003), Young and middle-aged scientific and technological innovation talents in Shenyang (No. RC220070). Thanks for kindly replies of Prof. Dong. Meta-analysis date of PROSPERO registration: This study was registered in the International Prospective Register of Systematic Reviews under identifier CRD42023387481 on January 3, 2023. 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Greenbaum L, Pode-Shakked B, Eisenberg-Barzilai S, Dicastro-Keidar M, Bar-Ziv A, Goldstein N, et al.Evaluation of Diagnostic Yield in Fetal Whole-Exome Sequencing: A Report on 45 Consecutive Families. Front Genet. 2019;10:425. Rinaldi B, Race V, Corveleyn A, Van Hoof E, Bauters M, Van Den Bogaert K, et al.Next-generation sequencing in prenatal setting: Some examples of unexpected variant association. Eur J Med Genet. 2020;63(5):103875. Aarabi M, Sniezek O, Jiang H, Saller DN, Bellissimo D, Yatsenko SA, et al.Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137(2):175-81. Heide S, Spentchian M, Valence S, Buratti J, Mach C, Lejeune E, et al.Prenatal exome sequencing in 65 fetuses with abnormality of the corpus callosum: contribution to further diagnostic delineation. Genet Med. 2020;22(11):1887-91. She Q, Tang E, Peng C, Wang L, Wang D, Tan W . Prenatal genetic testing in 19 fetuses with corpus callosum abnormality. J Clin Lab Anal. 2021;35(11):e23971. She Q, Zhen L, Fu F, Lei TY, Li LS, Li R, et al.[Prenatal genetic diagnosis of the fetuses with isolated corpus callosum abnormality]. Zhonghua Fu Chan Ke Za Zhi. 2022;57(9):671-7. Yang Y, Zhao S, Sun G, Chen F, Zhang T, Song J, et al.Genomic architecture of fetal central nervous system anomalies using whole-genome sequencing. NPJ Genom Med. 2022;7(1):31. Drexler KA, Talati AN, Gilmore KL, Veazey RV, Powell BC, Weck KE, et al.Association of deep phenotyping with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities. Genet Med. 2023;25(10):100915. Atwal PS, Brennan ML, Cox R, Niaki M, Platt J, Homeyer M, et al.Clinical whole-exome sequencing: are we there yet? Genet Med. 2014;16(9):717-9. Jacobsen JOB, Kelly C, Cipriani V, Research Consortium GE, Mungall CJ, Reese J, et al.Phenotype-driven approaches to enhance variant prioritization and diagnosis of rare disease. Hum Mutat. 2022;43(8):1071-81. Shi P, Liang H, Hou Y, Chen D, Ren H, Wang C, et al.The uncertainty of copy number variants: pregnancy decisions and clinical follow-up. Am J Obstet Gynecol. 2023;229(2):170.e1-.e8. Leu C, Balestrini S, Maher B, Hernández-Hernández L, Gormley P, Hämäläinen E, et al.Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy. EBioMedicine. 2015;2(9):1063-70. Tables Table 1. Diagnostic variants identified by ES of 36 cases. Case Prenatal Imaging findings Gene Transcript Variant(s) Amino acid change Zygosity Inheritance pattern Classification Related disease Pregnant outcome 1 Agenesis of cerebellar vermis CPLANE1 NM_023073.3 c.7978C>A p.Arg2660Ter Het mat AR LP Joubert syndrome17 TOP c.7169delT p.Ile2390Lysfs*44 Het pat AR LP 2 Agenesis of corpus callosum PDHA1 NM_000284.4 c.117+1_117+5del Splice acceptor variant Het XLD P Pyruvate Dehydrogenase E1α Deficiency TOP 3 Microcephaly ASPM NM_018136.5 c.7782_7783del p.Lys2595Serfs*6 Het mat AR P Congenital Microcephaly 5 TOP c.1853_1856del Het pat AR P 4 Microcephaly CEP135 NM_025009.5 c.703G>T p.Glu235Ter Het pat AR LP Congenital Microcephaly 8 TOP c.1252C>T p.Arg418Ter Het mat AR LP 5 Bilateral ventriculomegaly DLL1 NM_005618.4;exon c.118dup p.Cys63TrpfsTer63 Het (de novo) AD P NEDBAS TOP 6 Exencephaly PPP1R12A NM_002480.3 c.2129_2130del p.Thr710Asnfs*15 Het (de novo) AD P Brain Abnormalities syndrome TOP 7 Left ventriculomegaly,Irregular skull shape,Left hydronephrosis,Polyhydramnios AR NM_000044.6 c.1847G>A p.Arg616His Het mat XLR LP Androgen Insensitivity syndrome Healthy 8 Meningocele,Polycystic kidney,Oligohydramnios,Polydactyly CC2D2A NM_001080522.2 c.4179G>A p.Pro815Leufs*1 Het pat AR P Meckel syndrome 6 TOP c.2443delC Het mat AR P 9 Encephalocele,Bilateral polycystic kidney,Abnormal finger morphology TMEM67 NM_153704.6 c.579_580delAG p.Gly195Ilefs*13 Het mat AR P Meckel syndrome 3 TOP c.1646G>T p.Arg549Leu Het pat AR LP 10 Thin brain sulci and gyri,Irregular skull shape FAM111A NM_022074.3 c.1582G>C p.Asp528His Het (de novo) AD LP Elongated Bone Dysplasia Healthy 11 Hydrocephalus,Hydrops fetalis,Cardiac structure malformation,Pericardial effusion,Right talipes equinovarus COL4A1 NM_002347 c.324+1G>A splice_acceptor variant Het (de novo) AD P Porencephaly 1 TOP 12 Bilateral ventriculomegaly,Cleft palate,Alveolar cleft,Congenital heart defect CHD7 NM_017780.4,exon19 c.4393C＞T p.Arg1465Ter Het (de novo) AD P CHARGE syndrome TOP 13 Occipital encephalocele,Polycystic kidney,Polydactyly TMEM231 NM_001077416.2 c.747_748insTCCC p.Val250Serfs*11 Het pat AR LP Meckel syndrome 1 TOP c.742-2_744delAGATAc.425T>C p.Phe142Ser Het pat AR LP 14 Left ventriculomegaly,Abnormal signals of corpus callosum,Thick blood vessels,Intracranial high-level echo point TREX1 NM_033629.6;exon2 c.293dupA p.Cys99Metfs*3 Het mat AR LP Aicardi-Goutieres syndrome Healthy c.352C>G p.Pro118Ala Het pat AR LP 15 Enlarged posterior fossa,Echo heterogenicity of thalamus TREX1 NM_033629.6;exon2 c.294dup p.Cys99MetfsTer3 Homo AD P Aicardi-Goutieres syndrome Healthy 16 Agenesis of cavum septum pellucidum,Agenesis of corpus callosum,Cortical dysplasia,Narrowing or atresia of the digestive tract,Polyhydramnios,Enlarged of the left adrenal gland SMC1A NM_006306.4 c.2076delA p.Lys692Asnfs*27 Het (de novo) XLD P Cornelia De Lange syndrome2 TOP 17 Spina bifida meningocele,Abdominal wall defect,Cystocele,NT thickness VANGL2 NM_020335.3;exon4 c.740C>T p.Thr247Met Het mat AD LP Neural Tube Defect TOP 18 Bilateral ventriculomegaly PIK3CA NM 006218.4;exon21 c.31040>T p.Ala1035Val Het (de novo) AD p Megalcncephaly-capillary malfomation TOP 19 Bilateral ventriculomegaly ACO2 NM_ 001098.3;exonS c.561del p.Leul88 Ter Het mat AR LP Infantile cerebellar-retinal degeneration TOP 20 Bilateral ventriculomegaly AP571 NM 014855.3;cxon16 c.2079dup p. Pro694SerfsTer69 Het pat AR LP Spastic paraplegia 48, (AR) TOP 21 Unilateral ventriculomegaly FGFR3 NM 0001|42.5,exon12 c. 1620C>A p.AsnS40Lys Het pat AR P SADDAN TOP 22 Agenesis of corpus callosum L1CAM NM_001278116.2;in trong c.991+1G>T Shear mutation Hemi mat XLR LP Corpus callosum, partial agenesis of TOP 23 Agenesis of corpus callosum SMC1A NM_006306.4;exon22 c.3344G>T p.Cysl 115Phe Het (de novo) XLR P Developmental and epileptic encephalopathy 85, with or without midline brain defects TOP 24 Thin brain sulci and gyri，cortical dysplasia PEX6 NM_0002874,exonl c.87G>A p.Trp29 Ter Homo AR P Peroxisome biogenesis disorder 4A (Zellweger) TOP 25 Bilateral ventriculomegaly，Bilateral lens opacities OCRL NM_000276.4;exon18 c.1954-1958dup p.Glu654ArgfsTer18 Homo XLR P Dent disease 2 Healthy 26 Bilateral ventriculomegaly，Short femur FGFR3 NM 0001 42.5;exon9 c. 1138G>A p.Gly380Ang Het (de novo) AD P Thanatophoric dysplasia, type II TOP 27 Bilateral ventriculomegaly，crossed ectopic kidney SMS NM 004595.5; c. 166G>A p.Gly56Ser Hemi mat XLR LP Intellectual developmental disorder, X-linked syndromic, Snyder-Robinson type TOP 28 Bilateral ventriculomegaly，Vertebral cleft CHD7 NM 017780.4;exon26 c.5464G>A p.Gly 1822Ser Het (de novo) AD P CHARGE syndrome TOP 29 Bilateral ventriculomegaly RARS2 NM 020320.5；exon18 C. 1564G>A p.Val522lle Het mat AR LP Pontocerebellar hypoplasia, type 6 TOP 30 Unilateral ventriculomegaly NOTCH2 NM 024408.4;exon8 c. 1354C>T p.Arg452Cys Het (de novo) AD LP Hajdu-Cheney syndrome Healthy 31 Agenesis of corpus callosum KMT2A NM_001197104.2;exon27 c.797SC>T p.Arg2659Ter Het mat AD P Wiedemann-Steiner syndrome TOP 32 Enlarged posterior fossa KCNQ1 NM 000218.3:exon3 c.568C>T p.Arg190Trp Het mat AD LP Long QT syndrome 1 TOP 33 Enlarged posterior fossa TCF12 NM 207037.2:exon19 c.1969C>T p.Gln657Ter Het (de novo) AD P Craniosynostosis 3 TOP 34 Agenesis of cerebellar vermis COL4A1 NM 001845.6exon30 c. 2263G>A p.Gly755Arg Het (de novo) AD P Microangiopathy and leukoencephalopathy, pontine, autosomal dominant TOP 35 Brain and cardiac sarcoidosis TSC2 NM_000548.5;exon10 c.973C>T p.Gln325Ter Het (de novo) AD P Tuberous sclerosis-2 TOP 36 Agenesis of corpus callosum PTPN11 NM 002834.5；exon3 c.172A>C p.Asn58His Het (de novo) AD P Noonan syndrome 1 TOP ES, exome sequencing; M, male; Het, heterozygous; mat, maternal; pat, paternal; AR, autosomal recessive; LP, likely pathogenic; TOP, termination of pregnancy; F, female; XLD, X-linked dominant; P, pathogenic; NA, not applicable; AD, autosomal dominant; XLR, X-linked recessive; Homo, homozygous. Table 2. The findings of diagnostic yield based on the category of CNS abnormalities. Phenotype classification Risk difference Sample size P/LP findings in ES I. Isolated CNS anomaly 0.13 151 20 Neural tube defects 0.05 21 1 Microcephaly 0.22 9 2 Midline disorders 0.28 18 5 agenesis of the corpus callosum 0.31 16 5 holoprosencephaly 0.00 2 0 Posterior fossa disorders 0.17 23 4 Parenchymal defect 0.14 7 1 Ventricular anomalies 0.10 68 7 Intracranial hemorrhage 0.00 2 0 Arachnoid cyst 0.00 3 0 II. Multiple CNS anomalies 0.15 13 2 III.CNS combined with other system anomalies 0.25 55 14 Isolated CNS anomaly with other systems 0.28 47 13 Neural tube defects 0.33 12 4 Ventricular anomalies 0.33 21 7 Posterior fossa disorders 0.00 4 0 Midline disorders 0.00 2 0 Parenchymal defect 0.33 3 1 Others 0.20 5 1 Multiple CNS anomalies with other systems 0.125 8 1 Total 0.16 219 36 CNS, central nervous system; P, pathogenic; LP, likely pathogenic. Table 3. Pooled incremental yields of ES in specific phenotype anomaly of meta-analysis. Group Study numbers Sample size Positive numbers Pooled diagnostic yield (95%CI) I 2 P value I. Midline overall 15 209 57 0.28 (0.17,0.39) 51.17% 0.01 isolated 11 177 46 0.24 (0.17,0.31) 44.39% 0.05 multisystem 5 22 13 0.64 (0.39,0.85) 45.23% 0.12 a. Agenesis of corpus callosum overall 10 166 46 0.29 (0.18,0.42) 52.25% 0.03 isolated 10 155 39 0.25 (0.14,0.38) 51.36% 0.03 multisystem 3 15 11 0.68 (0.34,0.96) 36.54% 0.21 b. Holoprosencephaly overall 3 21 5 0.10 (0.00,0.30) 0.00% 0.54 II. Posterior cranial fossa overall 10 89 21 0.20 (0.11,0.30) 25.48% 0.21 isolated 7 58 12 0.17 (0.07,0.30) 11.23% 0.34 multisystem 4 26 9 0.32 (0.13,0.53) 16.52% 0.31 Dandy-walker syndrome overall 4 20 5 0.21 (0.04,0.45) 16.14% 0.31 isolated 3 15 2 0.11 (0.00,0.35) 0.00% 0.5 Cerebellar dysplasia overall 6 31 8 0.24(0.08,0.44) 0.00% 0.78 isolated 4 12 3 0.20(0.00,0.54) 0.00% 0.57 multisystem 5 14 2 0.09(0.00,0.51) 53.31% 0.07 III. Neural tube defect overall 7 86 11 0.12 (0.00,0.35) 71.38% 0.00 isolated 4 53 1 0.00 (0.00,0.05) 0.00% 0.73 multisystem 4 27 7 0.21 (0.06,0.41) 43.79% 0.15 IV. Ventriculomegaly overall 10 231 34 0.10 (0.05,0.15) 40.85% 0.09 isolated 5 176 19 0.08 (0.04,0.14) 18.80% 0.29 multisystem 6 49 13 0.23 (0.11,0.38) 0.00% 0.49 V. Microcephaly overall 4 27 4 0.12 (0.01,0.30) 0.00% 0.72 isolated 3 23 4 0.15 (0.02,0.36) 0.00% 0.56 VI. Cerebral haemorrhage overall 4 22 2 0.04 (0.00,0.20) 18.63% 0.3 isolated 3 19 2 0.04 (0.00,0.23) 25.01% 0.26 Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.docx Additional file 1. PRISMA Checklist. Additionalfile2.docx Additional file 2. The characteristics of the included studies. Additionalfile3.docx Additional file 3. Genes and disease. Additionalfile4.docx Additional file 4. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5459992","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":390243308,"identity":"e0b4cc10-1371-4eb1-a507-db91b469e9c6","order_by":0,"name":"Miss Jia Yao","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Miss","middleName":"Jia","lastName":"Yao","suffix":""},{"id":390243309,"identity":"5a78af78-d8fa-4db7-8717-1ebfbeb69a96","order_by":1,"name":"Yan Wang","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Wang","suffix":""},{"id":390243310,"identity":"ca84be64-8637-4b85-9cdb-2f344b20938d","order_by":2,"name":"DR. Gang Li","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"DR.","firstName":"Gang","middleName":"","lastName":"Li","suffix":""},{"id":390243311,"identity":"05ab9b06-e969-47f4-b69d-7e4e094a9aa3","order_by":3,"name":"Zhitao Zhang","email":"","orcid":"","institution":"Shenyang Women's and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhitao","middleName":"","lastName":"Zhang","suffix":""},{"id":390243312,"identity":"2082a8d9-f22e-451a-b0d4-b73e5ac60ab6","order_by":4,"name":"Yuan Lv","email":"","orcid":"","institution":"Shenyang Women's and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Lv","suffix":""},{"id":390243313,"identity":"3f35fe65-1afc-4218-b57b-34d3984bd125","order_by":5,"name":"Lizhu Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYDACdsYGIGnBwM8AZhADmMEqJRgkG4jXAiYlGAwOEOsu/mbmxg8faiTsjc8fbnvwg8FOTpeQZRKHGZslZxyTYDa7kdhu2MOQbGxG0LrDjG3MvA0SbGY3GNskeBgOJG4jpEUepOVvgwSPcf/BNsk/xGgxAGlhbJCQMGBIbJMmyhZDkF96jkkYSNwAapExIMIvcsfbH374UWNjz99//Jnkmwo7OcLeR3MnacpHwSgYBaNgFOAAAB5kOq/KW/fGAAAAAElFTkSuQmCC","orcid":"","institution":"China Medical University","correspondingAuthor":true,"prefix":"","firstName":"Lizhu","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-11-15 11:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5459992/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5459992/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71799381,"identity":"07380e84-b1f5-4239-99b2-61217e71a5dc","added_by":"auto","created_at":"2024-12-18 16:35:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":690677,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow chart of search and selection process\u003c/p\u003e\n\u003cp\u003eCNS, central nervous system; CMA, chromosomal microarray analysis.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5459992/v1/ccf042c4a7585419fd28e773.png"},{"id":71799385,"identity":"3791ecfc-aba0-434b-9af7-6f08c1557460","added_by":"auto","created_at":"2024-12-18 16:35:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":468981,"visible":true,"origin":"","legend":"\u003cp\u003eQuality assessment of studies included in systematic review.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eCMA, chromosomal microarray analysis; TAT, turnaround time; ACMG, American College of Medical Genetics and Genomics.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5459992/v1/4ed80583873f239d97fba696.png"},{"id":71800427,"identity":"79808618-bddf-47ea-b236-c8ab722de2a3","added_by":"auto","created_at":"2024-12-18 16:43:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":317871,"visible":true,"origin":"","legend":"\u003cp\u003ePooled incremental yields of ES.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5459992/v1/f30471d0177e93e6e3513aa0.png"},{"id":71801031,"identity":"745371b2-0a64-476a-a6e7-4b71c5e8a3ef","added_by":"auto","created_at":"2024-12-18 16:51:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2312737,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5459992/v1/611026f0-23dc-4413-bf0b-23d633851714.pdf"},{"id":71800428,"identity":"3a011fae-878e-4f6a-957c-c40219712b5f","added_by":"auto","created_at":"2024-12-18 16:43:50","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23053,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 1. PRISMA Checklist.\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5459992/v1/8f5b4918826c37806e8c3147.docx"},{"id":71799379,"identity":"79256af3-b954-454c-ba8d-a1e77774f78d","added_by":"auto","created_at":"2024-12-18 16:35:50","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":21324,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 2. The characteristics of the included studies.\u003c/p\u003e","description":"","filename":"Additionalfile2.docx","url":"https://assets-eu.researchsquare.com/files/rs-5459992/v1/4b46b9c1f1735d8c0bf0ca45.docx"},{"id":71800426,"identity":"d1496929-9dfd-485e-bd18-94259bf34c4d","added_by":"auto","created_at":"2024-12-18 16:43:50","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":26807,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 3. Genes and disease.\u003c/p\u003e","description":"","filename":"Additionalfile3.docx","url":"https://assets-eu.researchsquare.com/files/rs-5459992/v1/1ca6667bfc508c0b6557463b.docx"},{"id":71799382,"identity":"9637ae22-4f3b-4216-b744-9744d6b159db","added_by":"auto","created_at":"2024-12-18 16:35:50","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":13806,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 4. Search strategy\u003c/p\u003e","description":"","filename":"Additionalfile4.docx","url":"https://assets-eu.researchsquare.com/files/rs-5459992/v1/acd4879d440fb18f295730c5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prenatal Exome Sequencing of Fetuses with Central Nervous System Anomalies Based on Prenatal Ultrasound and Magnetic Resonance Imaging Diagnosis — A Retrospective Cohort Study and System Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCentral nervous system (CNS) abnormalities, constituting 9% of fetal malformations, significantly impact perinatal death, potentially affecting quality of life depending on severity. \u003csup\u003e(1)\u003c/sup\u003e Prenatal imaging (ultrasound and magnetic resonance imaging [MRI]) identifies various CNS abnormalities. \u003csup\u003e(2\u0026ndash;4)\u003c/sup\u003e However, genomic variations are often overlooked; therefore, in many cases, relying solely on imaging diagnosis is incomplete. Karyotyping and chromosomal microarray analysis (CMA) are routine invasive prenatal diagnostic methods that detect aneuploidy and pathogenic copy number variants (CNVs), \u003csup\u003e(5\u0026ndash;8)\u003c/sup\u003e with a diagnostic rate of approximately 6.2\u0026ndash;10.4% for CNS abnormalities. \u003csup\u003e(9\u0026ndash;11)\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eExome sequencing (ES), a next-generation technique, analyzes single nucleotide variants (SNVs) insertions and deletions and gene-coding regions to identify gene-level malformations. \u003csup\u003e(12, 13)\u003c/sup\u003e Compared to CMA, ES provides a 5\u0026ndash;66% increase in overall prenatal abnormalities, \u003csup\u003e(14\u0026ndash;22)\u003c/sup\u003e as a result, ES is increasingly used for fetuses with structural abnormalities and normal CMA results. However, detection rates varied significantly across different studies, potentially due to small sample sizes and a lack of diagnostic yield for various phenotypes.\u003c/p\u003e \u003cp\u003eThis study was undertaken to detect the incremental yield of ES over negative CMA through a cohort study and meta-analysis of fetal CNS malformations. Furthermore, we sought to evaluate the value of ES in various CNS anomaly phenotypes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCohort Study\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study, conducted from July 2020 to September 2023, focused on fetal CNS anomalies identified through prenatal ultrasound and MRI at Shengjing Hospital, a tertiary referral center for fetal anomalies affiliated with China Medical University. ES was recommended when CMA tests were non-diagnostic. Genetic counseling was provided to pregnant women and their families, explaining the necessity, limitations, and residual risks of genetic testing. After informed consent was obtained, genomic DNA was extracted from amniotic cells using the QIAGEN DNA Midi/Mini Kit according to the manufacturer\u0026apos;s protocol. This study was approved by the Hospital Ethics Committee of Shengjing Hospital, China Medical University.\u003c/p\u003e\n\u003cp\u003eSequencing involving 219 cases was performed using a NovaSeq 6000 sequencer (Illumina, San Diego, CA, USA) with 150-bp paired-end reads. The entire bioinformatics pipeline, from FASTQ files to the final report, was constructed using the GeneX Genetic Analysis Platform (Basecare Medical Co., Ltd.). FASTQ files were aligned against the hg19/GRCh37 reference genome using BWA v.0.7.17. \u003csup\u003e(23)\u0026nbsp;\u003c/sup\u003eVariant calling for SNVs and indels was performed using Genome Analysis Toolkit v.4.1.8.0. \u003csup\u003e(24)\u003c/sup\u003e Alongside SNVs and small indels, the GeneX pipeline detects CNVs using base CNVs proprietary CNVs-caller, which utilizes coverage information and is expected to detect CNVs with a resolution of two exons in the heterozygous state and a single exon in the homozygous state. \u003csup\u003e(25)\u003c/sup\u003e The analysis required a minimum average coverage of 100\u0026thinsp;\u0026times; for sample inclusion. The family-case analysis considered various inheritance modes. The filtering process retained rare variants with minor allele frequency \u0026lt;10%, protein-altering variants, variants in coding regions or within 20\u0026thinsp;bp from splice junctions, and variants with high or medium aggregated quality scores.\u003c/p\u003e\n\u003cp\u003eGeneX prioritized variants based on pathogenicity and clinical information, transcribed into Human Phenotype Ontology (HPO) terms (https://hpo.jax.org/app/). Sequencing data analysis was performed using the Verita Trekker\u003csup\u003e\u0026reg;\u003c/sup\u003e Mutation Site Detection System and GATK (https://software.broadinstitute.org/gatk/). Variant annotation databases comprised population databases, prediction algorithms, and disease/phenotype databases, including OMIM (http://www.omim.org), ClinVar (http://www.ncbi.nlm.nih.gov/clinvar), HGMD (http://www.hgmd.org), and HPO. The report interpretation followed the American College of Medical Genetics and Genomics (ACMG) guidelines, categorizing mutations into pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), possibly benign, and benign. \u003csup\u003e(26)\u0026nbsp;\u003c/sup\u003eOnly P or LP diagnostic variants were included in the positive diagnostic group. Data reanalysis was performed upon the emergence of a new phenotype during the third trimester or postpartum follow-up. Newly discovered diagnostic variants were validated through Sanger sequencing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMeta-analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eProtocol and Registration\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol has been prospectively registered in PROSPERO (CRD42023387481). The meta-analysis followed the PRISMA guidelines. \u003csup\u003e(27)\u003c/sup\u003e (Table S1, S2)\u003c/p\u003e\n\u003ch3\u003e\u003cem\u003e\u003cu\u003eData Sources\u003c/u\u003e\u003c/em\u003e\u003c/h3\u003e\n\u003cp\u003eFrom January 2010 to December 2023, we electronically searched databases (Medline, Embase, Web of Science, and Cochrane) using a comprehensive strategy with relevant Medical Subject Headings terms and keywords, including (\u0026quot;Prenatal Diagnosis\u0026quot; OR \u0026quot;Fetal Diseases\u0026quot; OR \u0026quot;Fetal Development\u0026quot; OR \u0026quot;Congenital Abnormalities\u0026quot;) AND (\u0026quot;Whole Genome Sequencing\u0026quot; OR \u0026quot;Whole Exome Sequencing\u0026quot; OR \u0026ldquo;Exome sequencing\u0026rdquo; OR \u0026quot;DNA Sequence Analysis\u0026quot;). Additional file 4outlines the detailed search strategy. The reference lists of pertinent articles were reviewed manually, and experts in prenatal genomics were consulted to discover additional relevant studies.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eEligibility Criteria and Study Selection\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEligibility criteria for observational studies included studies involving more than three fetuses with CNS abnormalities, presenting clear fetal phenotypes, including variants classified as LP/P, causative of the fetal phenotype, and having non-diagnostic CMA results. Any missing information prompted email inquiries to the corresponding authors. Exclusions comprised case reports, opinion articles, or letters; studies lacking detailed phenotypes; studies utilizing gene panels; and studies with unextractable data after a request for additional information from corresponding authors. Two independent reviewers (Y. J. and W. Y.) evaluated the abstracts of pertinent studies, and full-text articles underwent review once the met the inclusion criteria. A third investigator (C. L. Z.) independently resolved any disagreements between the reviewers.\u003c/p\u003e\n\u003ch3\u003e\u003cem\u003e\u003cu\u003eData Collection\u003c/u\u003e\u003c/em\u003e\u003c/h3\u003e\n\u003cp\u003eTwo reviewers independently extracted data capturing study characteristics and outcomes. The extracted data encompassed the study site, publication timeline, inclusion criteria, detection methods, sample size, count of positive case, fetal anomalies, implicated genes, and associated syndromes or diseases.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eQuality Assessment\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eQuality of the study was assessed using the Standards for Reporting of Diagnostic Accuracy Studies (STARD) \u003csup\u003e(28)\u003c/sup\u003e with modifications. Key quality criteria included participants with non-diagnostic CMA results, Sanger sequencing, variants classified according to ACMG or other guidelines, a clear description of both positive and negative fetal phenotypes, and clearly defined inclusion criteria.\u003c/p\u003e\n\u003ch3\u003e\u003cem\u003e\u003cu\u003eData Synthesis and Statistical Analysis\u003c/u\u003e\u003c/em\u003e\u003c/h3\u003e\n\u003cp\u003eCases were divided into three groups based on CNS abnormalities and extra-CNS abnormalities, as follows: isolated CNS abnormality (one CNS abnormality), multiple CNS abnormalities (two or more CNS abnormalities), and multisystem anomalies (CNS combined with other system abnormalities). Further division into the following six subgroups was based on HPO categories: midline malformations (aplasia of the corpus callosum, holoprosencephaly), anomaly of posterior cranial fossa (Dandy\u0026ndash;Walker malformation, cerebellar dysplasia), neural tube defects (NTDs), ventriculomegaly, microcephaly, and intracerebral hemorrhage.\u003c/p\u003e\n\u003cp\u003eExtracted results were pooled for meta-analysis, and ES diagnostic yield was calculated through single-scale analysis. \u003csup\u003e(29)\u0026nbsp;\u003c/sup\u003eThe Clopper\u0026ndash;Pearson exact method of a random- (I\u003csup\u003e2\u003c/sup\u003e\u0026ge;50) or fixed- (I\u003csup\u003e2\u003c/sup\u003e\u0026lt; 50) effect model was employed,\u003csup\u003e\u0026nbsp;(30)\u0026nbsp;\u003c/sup\u003eusing tau2, \u0026chi;2, and I\u003csup\u003e2\u003c/sup\u003e statistics to evaluate between-study heterogeneity/variability. Results were assessed through forest plots. Publication bias was assessed using funnel plots, \u003csup\u003e(31-33)\u003c/sup\u003e quantified using the Egger method (a weighted linear regression of the effect to its standard error) \u003csup\u003e(34)\u003c/sup\u003e, and adjusted for selection bias using the Copas model. \u003csup\u003e(35, 36)\u003c/sup\u003e Statistical analyses were performed with STATA 16. (https://www.stata.com/). Two reviewers (Y.J. and W.Y.) independently measured the risk of bias.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCohort Study\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eCohort Characteristics\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA cohort of 219 cases of fetal CNS abnormalities were collected whose CMA were nondiagnostic. The median gestational age was 25 (12-37) weeks and the median age of pregnant women was 31 (22-41) years. The median turnaround time (TAT) for ES was 21 days. \u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003e\u003cu\u003eES Detection Rate\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eP/LP sequence variants were detected in 16% (36/219) cases. The highest detection rate was observed in multisystem malformation (26%, 14/55), followed by multiple CNS anomalies (15%, 2/13) and isolated CNS anomaly (13%, 20/151). Detailed information on the 36 cases with positive ES results is presented in Table 1. In isolated CNS malformations, positive results mainly occurred in agenesis of the corpus callosum (29%, 5/18), while choroid plexus cysts were associated with negative results (0%, 0/3), although the sample size was limited. Table 2 shows the findings of the diagnostic yield based on the category of CNS abnormalities. In addition, five cases of VUS were identified.\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003e\u003cu\u003eAssociated Extra-CNS Abnormalities\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAlthough skeletal abnormalities (49%) were the most common associated abnormalities, cases with urogenital (50%) and cardiovascular (33%) abnormalities showed significantly higher detection rates. In particular, NTD\u003cstrong\u003es\u003c/strong\u003e combined with urogenital anomalies were significantly associated with positive ES results (57%, 4/7).\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003e\u003cu\u003eGenetic Characteristics\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong the diagnosed variants, 44% exhibited an autosomal recessive (AR) inheritance pattern, 40% exhibited an \u003cem\u003eautosomal dominant \u003c/em\u003e\u003cem\u003e(AD) \u003c/em\u003einheritance pattern, 11% exhibited an X-linked recessive (XLR)\u003cem\u003e \u003c/em\u003einheritance pattern and 5% exhibited an X-linked \u003cem\u003edominant \u003c/em\u003e\u003cem\u003e(XLD) \u003c/em\u003einheritance pattern. Among the positive cases, 65% were inherited mutations and 35% were de novo mutations. Furthermore, seven new variation sites were identified in six genes) (PDHA1, TMEM231, CPLANE1, CC2D2A, TREX1, CEP135). The most common syndromes in positive cases were Meckel syndrome (3/36, 8%), Congenital Microcephaly (2/36, 6%) and Aicardi-Goutieres syndrome (2/36, 6%), with the remaining cases occurring once each (n=29). \u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003e\u003cu\u003ePregnancy Outcome\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe most common pregnancy outcome was termination of pregnancy (83.1%, n = 182/219). Patients whose fetuses had a P/LP mutation (83.3%, 30/36) were more likely to terminate than those with undiagnostic results (83.1%, 152/183); however, the difference was not statistically significant (P = 0.83). \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMeta-analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ch3\u003e\u003cem\u003e\u003cu\u003eStudy Selection and Characteristics\u003c/u\u003e\u003c/em\u003e\u003c/h3\u003e\n\u003cp\u003eA total of 1879 records were identified in the database search. After screening the abstract, 113 articles were assessed, of which 21 met the inclusion criteria \u003csup\u003e(18-22, 37-52)\u003c/sup\u003e along with our cohort study. Twenty-two studies (989 cases) were included in the meta-analysis (Figure 1), among which 9 were prospective and 13 were retrospective. Seventeen series used Trio-ES, and five employed proband-ES and Trio-ES. Average gestational and maternal ages were 21 (12\u0026ndash;37) weeks and 31 (22\u0026ndash;41) years, respectively. The median TAT was 22 (4\u0026ndash;56) days. The most common pregnancy outcome with positive results was termination of pregnancy (86.0%, 135/157). Study characteristics are detailed in Additional file 2. Figure 2 presents the overall quality assessment using modified STARD criteria.\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003e\u003cu\u003eSynthesis of \u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u003cu\u003eR\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u003cu\u003eesults and \u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u003cu\u003eR\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u003cu\u003eisk of \u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u003cu\u003eB\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u003cu\u003eias\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 238 cases were identified of P or LP variants. The detection rates of general meta-analysis were: (1) the overall CNS anomaly: 27% [95% confidence interval (CI), 21-34%]; (2) Isolated CNS anomaly: 16% [95% (CI), 10-22%]; (3) Multiple CNS anomalies: 26% [95% (CI), 10-44%]; (4) multisystem anomalies: 35% [95% (CI), 29-41%] (Figure 3.). The pooled diagnostic yield of specific abnormal phenotypes is presented in detail in Table 3. In cases of complex CNS abnormalities, the positive diagnostic rate for fetuses with three or more CNS anomalies [43% (95% confidence interval, 31-58%)] differed significantly from that for those with two CNS anomalies [10% (95% confidence interval, 4-18%)]. Isolated NTDs are closely related to the negative results of ES, with a detection rate of 0% [95% (CI), 0-5%]. Of the 53 cases of isolated NTDs, only one case from our cohort study identified a pathogenic de novo SNV. The pooled detection rate of VUS was 5% [95% (CI), 1-11%]. The diagnostic yield for CNS abnormalities identified by prenatal MRI combined with ultrasound and by ultrasound alone showed no statistical difference [27% (95% confidence interval, 20-36%)] vs [25% (95% confidence interval, 17-35%)]. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003e \u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eGenetic Characteristics\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 238 cases with a positive molecular ES diagnosis, 246 variants from 137 genes were identified, with 46 occurring more than once. The frequently affected genes were L1CAM (n=10), TUBA1A (n=10) and CHD7 (n=8). Inherited mutations (58%) were the most common origin of pathogenic genes, with AD inheritance presenting the highest proportion (46%). The predominant syndromes detected were Meckel\u0026ndash;Gruber syndrome (n=15) and lissencephaly (n=13) (Additional file 3). \u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003e\u003cu\u003eAssociated Extra-CNS Abnormalities\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSkeletal abnormalities were the most prevalent association with CNS anomalies (45%). Among positive cases, CNS anomalies combined with NT thickening (56%), urogenital abnormalities (56%), and eyes abnormalities (55%) presented the highest diagnostic rate. Among the different phenotypes, corpus callosum anomalies combined with facial abnormalities (73%) and NTDs combined with urogenital malformations (80%) showed the highest detection rate. No significant difference was found between the diagnostic rate of CNS anomalies combined with one extra-CNS system abnormality [29% (95% confidence interval, 20-39%)] and that of CNS anomalies combined with two or more system abnormalities [45% (95% confidence interval, 32-58%)].\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrincipal Findings\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur cohort study and meta-analysis underscore the significant additional diagnostic yield of ES over CMA, suggesting its high efficacy in detecting prenatal CNS anomalies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResults in the Context of What is Known\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs Tolusso et al. \u003csup\u003e(18)\u003c/sup\u003e reported, ES played a vital role in assessing recurrence risk and guiding perinatal care. The results of our study suggested that ES had little effect on the current pregnancy outcome, but it had important guiding significance for the next pregnancy. Over half of the diagnosed cases in our study carried a significant recurrence risk, providing valuable information for future reproductive options, including prenatal diagnosis or preimplantation genetic testing. By identifying potential pathogenic mutations, exome sequencing can help parents understand genetic risks and make more informed decisions in future pregnancies. In addition, the gradual decrease in the TAT of ES (the average TAT reported in 2014 was 18 weeks, \u003csup\u003e(53)\u003c/sup\u003e and the average TAT in the meta-analysis was 22 days) may increase the practicality of ES in prenatal genetic testing.\u003c/p\u003e\n\u003cp\u003eES suitability as the primary prenatal genetic test for CNS abnormalities remains debated owing to its advantages and limitations. Tan et al. \u003csup\u003e(20)\u0026nbsp;\u003c/sup\u003esuggested using ES after obtaining negative CMA and karyotyping results. However, Yaron et al. \u003csup\u003e(19)\u0026nbsp;\u003c/sup\u003erecommended ES as the first-level prenatal diagnosis for major CNS abnormalities, as it provided a high diagnostic yield (\u0026gt;50%)\u003cem\u003e.\u0026nbsp;\u003c/em\u003eOur results suggest that the use of ES should be prioritized in cases of three or more CNS abnormalities, or the coexistence of CNS malformations with other system malformations. Moreover, a cost assessment of ES is required to demonstrate its clinical cost-effectiveness.\u003c/p\u003e\n\u003cp\u003eDiagnostic yields varied among different phenotypes, with ES presenting a low incremental diagnostic yield for isolated NTDs in our meta-analysis. The etiology of NTDs is multifactorial, involving both environmental factors and various genetic and non-genetic factors. Therefore, in families with a history of recurrent neural tube defects, it is more appropriate to detect genes currently known to be associated with NTDs in order to better understand these potential genetic risks. The diagnostic yield of ES for multisystem abnormalities is related to the category of abnormalities, but there appears to be no significant difference based on the number of abnormalities. When CNS abnormalities are combined with urogenital abnormalities, eyes abnormalities, cardiovascular system anomalies, or increased NT, the diagnostic yield is higher. In cases of complex CNS abnormalities, our study suggests that the presence of more than three types of CNS abnormalities in a fetus is often indicative of a higher likelihood of SNVs. Owing to the differences in phenotypic diagnostic yields, accurate and comprehensive descriptions of abnormal phenotypes are important for genetic diagnosis. Phenotype-driven approaches can significantly improve molecular diagnosis and clinical consultation. \u003csup\u003e(54)\u003c/sup\u003e Standardizing the recording of phenotypes and expanding terms for prenatal discovery of HPO are essential, as they can enhance the elucidation of the relationship between phenotype and prognosis through ES.\u003c/p\u003e\n\u003cp\u003eIn our cohort study, we identified five cases (2%) with a VUS holding potential clinical relevance. The meta-analysis revealed a 5% increase in VUS yield, which may pose challenges to pregnancy decision-making. A recent cohort study by Shi et al. \u003csup\u003e(55)\u003c/sup\u003e demonstrated that 78% (108/139) of fetuses with VUS did not exhibit disease features post-birth. Most VUS were determined to be benign, presenting a low risk for adverse disease outcomes. Although most VUS may prove benign or unrelated, a small number will eventually emerge as P/LP owing to data-sharing tool update (Franklin Users Community \u003csup\u003e(56)\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFuture\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eC\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003elinical and\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eR\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eesearch\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eI\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003emplications\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn cases where three or more CNS abnormalities are present, or where CNS malformations coexist with abnormalities in other systems, ES should be considered the preferred option. The future clinical and research significance is to improve our understanding of phenotypic-genotypic relationships. For VUS variants, long-term postnatal follow-ups, postmortem fetal structure investigations, and genetic function studies can provide valuable information for clinical diagnosis and parental decision-making. Further research may also focus on the patient experience of undergoing ES during pregnancy, its impact on clinical diagnosis and parental decision-making processes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStrengths and Limitations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are several strengths to this study. Firstly, it encompassed exome sequencing of maternal-paternal-fetal trios, which aided in the determination of the pathogenicity of identified variants and the assessment of inheritance. All variants were reviewed by a multidisciplinary committee, enhancing the accuracy of variant interpretation. Moreover, all positive results were confirmed using Sanger sequencing in laboratories accredited by the revised standards for clinical laboratories. The studies included in the meta-analysis exhibited high quality, with most studies employing the ACMG classification for genetic variant interpretation and Sanger sequencing for validation. To minimize bias, we included studies with more than three cases in the meta-analysis.\u003c/p\u003e\n\u003cp\u003eThis study had some limitations. The relatively limited number of cases restricts the generalizability of conclusions regarding specific phenotype detection rates. Secondly, the review was comprehensive; however, despite employing a random-effects model, high heterogeneity persisted, with subgroup analysis indicating that this was mainly due to the diversity of phenotypes. Thirdly, certain disease processes might exhibit abnormalities later in pregnancy or the early neonatal period, and not all studies provided confirmed postpartum or post-mortem results, potentially leading to neglect of phenotypes and inaccuracies in classification within our review. Lastly, termination of pregnancy was chosen in 80% of cases, preventing further follow-up to investigate the prenatal and postnatal clinical effects of genetic testing benefits.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAccurate detection of CNS abnormalities is crucial for informed clinical decisions, given their profound impact on the development and quality of life of children. Combined with our cohort study, we systematically reviewed and analyzed the existing literature on ES for prenatal CNS abnormalities. The findings indicate that ES exhibited a high detection rate surpassing other fetal genetic assessment methods. Furthermore, the detection rates for different phenotypes are conducive to clinical consultation. ES is more effective and valuable for detecting genetic diseases than other clinical genetic testing methods, such as CMA. Our research provides a valuable tool for counseling and decision-making regarding reproductive options.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCNS Central nervous system\u003c/p\u003e\n\u003cp\u003eMRI Magnetic resonance imaging \u003c/p\u003e\n\u003cp\u003eCMA Chromosomal microarray analysis\u003c/p\u003e\n\u003cp\u003eCNVs Copy number variants\u003c/p\u003e\n\u003cp\u003eES Exome sequencing \u003c/p\u003e\n\u003cp\u003eSNVs Single nucleotide variants \u003c/p\u003e\n\u003cp\u003eHPO Human Phenotype Ontology \u003c/p\u003e\n\u003cp\u003eACMG American College of Medical Genetics and Genomics\u003c/p\u003e\n\u003cp\u003eP Pathogenic \u003c/p\u003e\n\u003cp\u003eLP Likely pathogenic\u003c/p\u003e\n\u003cp\u003eVUS Variant of uncertain significance\u003c/p\u003e\n\u003ch3\u003eSTARD Standards for Reporting of Diagnostic Accuracy Studies\u003c/h3\u003e\n\u003ch3\u003eNTDs Neural tube defects\u003c/h3\u003e\n\u003cp\u003eTAT Turnaround time \u003c/p\u003e\n\u003cp\u003eAR Autosomal recessive \u003c/p\u003e\n\u003cp\u003eAD Autosomal dominant \u003c/p\u003e\n\u003cp\u003eXLR X-linked recessive \u003c/p\u003e\n\u003cp\u003eXLD X-linked dominant\u003c/p\u003e\n\u003cp\u003eCI confidence interval\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll individuals participating in this study provided informed consent. The study was approved by the Research Ethics Committee of Shengjing Hospital, China Medical University (Ethical approval number: 2019PS493K).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Data Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China (NO.82272022), National Key Research and Development Program (2021YFC2701003), Young and middle-aged scientific and technological innovation talents in Shenyang (No. RC220070). Corresponding authors had full access to all the data in the study and final responsibility for the decision to submit for publication. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJia Yao: Software, Methodology, Formal analysis, Data curation, Investigation, Writing Original Draft\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYan Wang: Data curation, Formal analysis, Validation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGang Li: Investigation, Supervision\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZhitao Zhang: Case collection\u003c/p\u003e\n\u003cp\u003e*Yuan Lv: Conceptualization, Supervision, Writing-Review \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003e*Lizhu Chen: Conceptualization, Methodology, Supervision, Writing-Review \u0026amp; Editing\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the National Natural Science Foundation of China (NO.82272022), National Key Research and Development Program (2021YFC2701003), Young and middle-aged scientific and technological innovation talents in Shenyang (No. RC220070). Thanks for kindly replies of Prof. Dong.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeta-analysis date of PROSPERO registration:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was registered in the International Prospective Register of Systematic Reviews under identifier CRD42023387481 on January 3, 2023.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRouleau C, Gasner A, Bigi N, Couture A, Perez MJ, Blanchet P, et al.Prevalence and timing of pregnancy termination for brain malformations. Arch Dis Child Fetal Neonatal Ed. 2011;96(5):F360-4.\u003c/li\u003e\n\u003cli\u003eLimperopoulos C, Clouchoux C\u003cstrong\u003e. \u003c/strong\u003eAdvancing fetal brain MRI: targets for the future. Semin Perinatol. 2009;33(4):289-98.\u003c/li\u003e\n\u003cli\u003ePistorius LR, Hellmann PM, Visser GH, Malinger G, Prayer D\u003cstrong\u003e. \u003c/strong\u003eFetal neuroimaging: ultrasound, MRI, or both? 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J Endod. 2018;44(10):1467-73.\u003c/li\u003e\n\u003cli\u003eBiljana M, Jelena M, Branislav J, Milorad R\u003cstrong\u003e. \u003c/strong\u003eBias in meta-analysis and funnel plot asymmetry. Stud Health Technol Inform. 1999;68:323-8.\u003c/li\u003e\n\u003cli\u003eEgger M, Davey Smith G, Schneider M, Minder C\u003cstrong\u003e. \u003c/strong\u003eBias in meta-analysis detected by a simple, graphical test. Bmj. 1997;315(7109):629-34.\u003c/li\u003e\n\u003cli\u003eCopas J, Shi JQ\u003cstrong\u003e. \u003c/strong\u003eMeta-analysis, funnel plots and sensitivity analysis. Biostatistics. 2000;1(3):247-62.\u003c/li\u003e\n\u003cli\u003eCarpenter JR, Schwarzer G, R\u0026uuml;cker G, K\u0026uuml;nstler R\u003cstrong\u003e. \u003c/strong\u003eEmpirical evaluation showed that the Copas selection model provided a useful summary in 80% of meta-analyses. 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Genet Med. 2020;22(11):1887-91.\u003c/li\u003e\n\u003cli\u003eShe Q, Tang E, Peng C, Wang L, Wang D, Tan W\u003cstrong\u003e. \u003c/strong\u003ePrenatal genetic testing in 19 fetuses with corpus callosum abnormality. J Clin Lab Anal. 2021;35(11):e23971.\u003c/li\u003e\n\u003cli\u003eShe Q, Zhen L, Fu F, Lei TY, Li LS, Li R, et al.[Prenatal genetic diagnosis of the fetuses with isolated corpus callosum abnormality]. Zhonghua Fu Chan Ke Za Zhi. 2022;57(9):671-7.\u003c/li\u003e\n\u003cli\u003eYang Y, Zhao S, Sun G, Chen F, Zhang T, Song J, et al.Genomic architecture of fetal central nervous system anomalies using whole-genome sequencing. NPJ Genom Med. 2022;7(1):31.\u003c/li\u003e\n\u003cli\u003eDrexler KA, Talati AN, Gilmore KL, Veazey RV, Powell BC, Weck KE, et al.Association of deep phenotyping with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities. Genet Med. 2023;25(10):100915.\u003c/li\u003e\n\u003cli\u003eAtwal PS, Brennan ML, Cox R, Niaki M, Platt J, Homeyer M, et al.Clinical whole-exome sequencing: are we there yet? Genet Med. 2014;16(9):717-9.\u003c/li\u003e\n\u003cli\u003eJacobsen JOB, Kelly C, Cipriani V, Research Consortium GE, Mungall CJ, Reese J, et al.Phenotype-driven approaches to enhance variant prioritization and diagnosis of rare disease. Hum Mutat. 2022;43(8):1071-81.\u003c/li\u003e\n\u003cli\u003eShi P, Liang H, Hou Y, Chen D, Ren H, Wang C, et al.The uncertainty of copy number variants: pregnancy decisions and clinical follow-up. Am J Obstet Gynecol. 2023;229(2):170.e1-.e8.\u003c/li\u003e\n\u003cli\u003eLeu C, Balestrini S, Maher B, Hern\u0026aacute;ndez-Hern\u0026aacute;ndez L, Gormley P, H\u0026auml;m\u0026auml;l\u0026auml;inen E, et al.Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy. EBioMedicine. 2015;2(9):1063-70.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Diagnostic variants identified by ES of 36 cases.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"135%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003eCase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003ePrenatal Imaging findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eGene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eTranscript\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eVariant(s)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eAmino acid change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eZygosity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eInheritance pattern\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eClassification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eRelated disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ePregnant outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp\u003eAgenesis of cerebellar vermis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 6px;\"\u003e\n \u003cp\u003eCPLANE1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_023073.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.7978C\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Arg2660Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11px;\"\u003e\n \u003cp\u003eJoubert syndrome17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.7169delT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Ile2390Lysfs*44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eAgenesis of corpus callosum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ePDHA1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_000284.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.117+1_117+5del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eSplice acceptor variant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eXLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003ePyruvate Dehydrogenase E1\u0026alpha;\u0026nbsp;Deficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"50\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMicrocephaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 6px;\"\u003e\n \u003cp\u003eASPM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_018136.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.7782_7783del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Lys2595Serfs*6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11px;\"\u003e\n \u003cp\u003eCongenital Microcephaly 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.1853_1856del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMicrocephaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 6px;\"\u003e\n \u003cp\u003eCEP135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_025009.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.703G\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Glu235Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11px;\"\u003e\n \u003cp\u003eCongenital Microcephaly 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.1252C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Arg418Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eDLL1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_005618.4;exon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.118dup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Cys63TrpfsTer63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eNEDBAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eExencephaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ePPP1R12A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_002480.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.2129_2130del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Thr710Asnfs*15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eBrain Abnormalities syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eLeft ventriculomegaly,Irregular skull shape,Left hydronephrosis,Polyhydramnios\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_000044.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.1847G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Arg616His\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eXLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eAndrogen Insensitivity syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eHealthy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMeningocele,Polycystic kidney,Oligohydramnios,Polydactyly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 6px;\"\u003e\n \u003cp\u003eCC2D2A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_001080522.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.4179G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Pro815Leufs*1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11px;\"\u003e\n \u003cp\u003eMeckel syndrome 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"69\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.2443delC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp\u003eEncephalocele,Bilateral polycystic kidney,Abnormal finger morphology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 6px;\"\u003e\n \u003cp\u003eTMEM67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_153704.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.579_580delAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Gly195Ilefs*13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11px;\"\u003e\n \u003cp\u003eMeckel syndrome 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.1646G\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Arg549Leu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eThin brain sulci and gyri,Irregular skull shape\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eFAM111A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_022074.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.1582G\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Asp528His\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eElongated Bone Dysplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eHealthy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eHydrocephalus,Hydrops fetalis,Cardiac structure\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emalformation,Pericardial effusion,Right talipes equinovarus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eCOL4A1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_002347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.324+1G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003esplice_acceptor variant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003ePorencephaly 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"189\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly,Cleft palate,Alveolar cleft,Congenital heart defect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eCHD7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_017780.4,exon19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.4393C＞T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Arg1465Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eCHARGE syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 12px;\"\u003e\n \u003cp\u003eOccipital encephalocele,Polycystic kidney,Polydactyly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 6px;\"\u003e\n \u003cp\u003eTMEM231\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_001077416.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.747_748insTCCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Val250Serfs*11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 11px;\"\u003e\n \u003cp\u003eMeckel syndrome 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003ec.742-2_744delAGATAc.425T\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Phe142Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"55\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd height=\"55\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp\u003eLeft ventriculomegaly,Abnormal signals of corpus callosum,Thick blood vessels,Intracranial high-level echo point\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 6px;\"\u003e\n \u003cp\u003eTREX1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_033629.6;exon2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.293dupA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Cys99Metfs*3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11px;\"\u003e\n \u003cp\u003eAicardi-Goutieres syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003eHealthy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.352C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Pro118Ala\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEnlarged posterior fossa,Echo heterogenicity of thalamus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eTREX1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_033629.6;exon2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.294dup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Cys99MetfsTer3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eAicardi-Goutieres syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eHealthy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eAgenesis of cavum septum pellucidum,Agenesis of corpus callosum,Cortical dysplasia,Narrowing or atresia of the digestive tract,Polyhydramnios,Enlarged of the left adrenal gland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eSMC1A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_006306.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.2076delA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Lys692Asnfs*27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eXLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eCornelia De Lange syndrome2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eSpina bifida meningocele,Abdominal wall defect,Cystocele,NT thickness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eVANGL2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_020335.3;exon4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.740C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Thr247Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eNeural Tube Defect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ePIK3CA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 006218.4;exon21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.31040\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Ala1035Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eMegalcncephaly-capillary malfomation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eACO2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_ 001098.3;exonS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.561del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Leul88 Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eInfantile cerebellar-retinal degeneration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eAP571\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 014855.3;cxon16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.2079dup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep. Pro694SerfsTer69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eSpastic paraplegia 48, (AR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e21\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eUnilateral ventriculomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eFGFR3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 0001|42.5,exon12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec. 1620C\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.AsnS40Lys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet pat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eSADDAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eAgenesis of corpus callosum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eL1CAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_001278116.2;in trong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.991+1G\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eShear\u003c/p\u003e\n \u003cp\u003emutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHemi mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eXLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eCorpus callosum, partial agenesis of\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e23\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eAgenesis of corpus callosum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eSMC1A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_006306.4;exon22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.3344G\u0026gt;T\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Cysl 115Phe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eXLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eDevelopmental and epileptic\u0026nbsp;\u003cbr\u003e\u0026nbsp;encephalopathy 85, with or without midline brain defects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eThin brain sulci and gyri，cortical dysplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ePEX6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_0002874,exonl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.87G\u0026gt;A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Trp29 Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003ePeroxisome biogenesis disorder 4A (Zellweger)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly，Bilateral lens opacities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eOCRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_000276.4;exon18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.1954-1958dup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Glu654ArgfsTer18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eXLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eDent disease 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eHealthy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e26\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly，Short femur\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eFGFR3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 0001 42.5;exon9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec. 1138G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Gly380Ang\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eThanatophoric dysplasia, type II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e27\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly，crossed ectopic kidney\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eSMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 004595.5;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec. 166G\u0026gt;A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Gly56Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHemi mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eXLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eIntellectual developmental disorder, X-linked syndromic, Snyder-Robinson type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e28\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly，Vertebral cleft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eCHD7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 017780.4;exon26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.5464G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Gly 1822Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eCHARGE syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e29\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBilateral ventriculomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eRARS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 020320.5；exon18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eC. 1564G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Val522lle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003ePontocerebellar hypoplasia, type 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e30\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eUnilateral ventriculomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eNOTCH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 024408.4;exon8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec. 1354C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Arg452Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eHajdu-Cheney syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eHealthy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e31\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eAgenesis of corpus callosum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eKMT2A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_001197104.2;exon27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.797SC\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Arg2659Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eWiedemann-Steiner syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e32\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEnlarged posterior fossa\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eKCNQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 000218.3:exon3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.568C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Arg190Trp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet mat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eLong QT syndrome 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e33\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEnlarged posterior fossa\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eTCF12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 207037.2:exon19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.1969C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Gln657Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;Craniosynostosis 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e34\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eAgenesis of cerebellar vermis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eCOL4A1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 001845.6exon30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec. 2263G\u0026gt;A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Gly755Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;Microangiopathy and leukoencephalopathy, pontine, autosomal dominant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e35\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eBrain and cardiac sarcoidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eTSC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM_000548.5;exon10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.973C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Gln325Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;Tuberous sclerosis-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e36\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eAgenesis of corpus callosum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003ePTPN11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eNM 002834.5；exon3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ec.172A\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ep.Asn58His\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHet (de novo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eNoonan syndrome 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eTOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eES, exome sequencing; M, male; Het, heterozygous; mat, maternal; pat, paternal; AR, autosomal recessive; LP, likely pathogenic; TOP, termination of pregnancy; F, female; XLD, X-linked dominant; P, pathogenic;\u0026nbsp;NA, not applicable;\u0026nbsp;AD, autosomal dominant; XLR, X-linked recessive; Homo, homozygous.\u003c/p\u003e\n\u003cp\u003eTable 2. The findings of diagnostic yield based on the category of CNS abnormalities.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"106%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePhenotype\u0026nbsp;classification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eRisk\u0026nbsp;difference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eSample\u0026nbsp;size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eP/LP\u0026nbsp;findings\u0026nbsp;in\u0026nbsp;ES\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eI. Isolated\u0026nbsp;CNS\u0026nbsp;anomaly\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e151\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNeural\u0026nbsp;tube\u0026nbsp;defects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eMicrocephaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eMidline\u0026nbsp;disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cem\u003eagenesis of the corpus callosum\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cem\u003eholoprosencephaly\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePosterior\u0026nbsp;fossa\u0026nbsp;disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eParenchymal\u0026nbsp;defect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eVentricular\u0026nbsp;anomalies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eIntracranial\u0026nbsp;hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eArachnoid cyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eII. Multiple\u0026nbsp;CNS\u0026nbsp;anomalies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIII.CNS\u0026nbsp;combined\u0026nbsp;with\u0026nbsp;other\u0026nbsp;system\u0026nbsp;anomalies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eIsolated\u0026nbsp;CNS\u0026nbsp;anomaly\u0026nbsp;with\u0026nbsp;other\u0026nbsp;systems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNeural\u0026nbsp;tube\u0026nbsp;defects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eVentricular\u0026nbsp;anomalies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePosterior\u0026nbsp;fossa\u0026nbsp;disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eMidline\u0026nbsp;disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eParenchymal\u0026nbsp;defect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eMultiple\u0026nbsp;CNS\u0026nbsp;anomalies\u0026nbsp;with\u0026nbsp;other\u0026nbsp;systems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;CNS, central nervous system; P, pathogenic; LP, likely pathogenic.\u003c/p\u003e\n\u003cp\u003eTable 3. Pooled incremental yields of ES in specific phenotype anomaly of meta-analysis.\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"138%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroup\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u0026nbsp;\u003cbr\u003e\u0026nbsp;numbers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample\u0026nbsp;\u003cbr\u003e\u0026nbsp;size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive\u0026nbsp;\u003cbr\u003e\u0026nbsp;numbers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePooled diagnostic yield (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eI.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eMidline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.28 (0.17,0.39) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e51.17%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e177\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.24 (0.17,0.31) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e44.39%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003emultisystem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.64 (0.39,0.85) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e45.23%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cem\u003ea. Agenesis of\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ecorpus callosum\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.29 (0.18,0.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e52.25%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.25 (0.14,0.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e51.36%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003emultisystem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.68 (0.34,0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e36.54%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cem\u003eb. Holoprosencephaly\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.10 (0.00,0.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eII. Posterior cranial fossa\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.20 (0.11,0.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e25.48%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.17 (0.07,0.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e11.23%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003emultisystem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.32 (0.13,0.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e16.52%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cem\u003eDandy-walker syndrome\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.21 (0.04,0.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e16.14%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.11 (0.00,0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cem\u003eCerebellar dysplasia\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.24(0.08,0.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.20(0.00,0.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003emultisystem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.09(0.00,0.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e53.31%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIII. Neural tube defect\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.12 (0.00,0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e71.38%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00 (0.00,0.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003emultisystem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.21\u0026nbsp;(0.06,0.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e43.79%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIV. Ventriculomegaly\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e231\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.10 (0.05,0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e40.85%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.08 (0.04,0.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e18.80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003emultisystem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.23 (0.11,0.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eV. Microcephaly\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.12 (0.01,0.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.15 (0.02,0.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVI. Cerebral haemorrhage\u003c/strong\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eoverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.04 (0.00,0.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e18.63%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eisolated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e0.04 (0.00,0.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e25.01%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Central nervous system anomalies, Exome sequencing, Prenatal diagnosis, Fetus","lastPublishedDoi":"10.21203/rs.3.rs-5459992/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5459992/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAssessing the incremental yield of prenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) in the diagnosis of central nervous system (CNS) anomalies based on prenatal ultrasound and magnetic resonance imaging (MRI) diagnoses.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this retrospective cohort study, we collected the ES results of fetuses diagnosed with CNS anomalies through prenatal ultrasound and MRI between 2019 and 2023, who also had negative CMA results. We performed subgroup analyses to assess detection rates for different phenotypes in order to identify associated genes and variants. A meta-analysis combining our study with relevant research was performed to further explore the association between phenotype and ES.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the cohort study of 219 cases, ES identified pathogenic/likely pathogenic single nucleotide variations in 36 cases (16%). The highest detection rate was observed in cases with multisystem malformations (25%, 14/55), followed by multiple CNS anomalies (15%, 2/13) and isolated CNS anomaly (13%, 20/151). The most commonly identified isolated CNS anomaly was agenesis of the corpus callosum (31%, 5/16). Neural tube defects with urogenital anomalies were strongly linked to positive ES results (57%, 4/7). The meta-analysis of 989 cases from 22 studies showed a pooled ES diagnostic yield of 27% [(95% (CI), 21\u0026ndash;34%)]. The highest detection rates were in cases of corpus callosum anomalies with facial abnormalities (75%, 8/11) and neural tube defects with urogenital malformations (80%, 12/15). The detection rate for three or more types of complex central nervous system (CNS) abnormalities was 43% (95% confidence interval, 31%-58%), which was significantly higher than that for only two abnormalities, which was 10% [(95% (CI), 4%-18%). No significant difference in diagnostic yield was found between cases identified by prenatal MRI combined with ultrasound [27% (95% confidence interval, 20\u0026ndash;36%)] and those identified by ultrasound alone [25% (95% confidence interval, 17\u0026ndash;35%)].\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eES provided a significantly higher diagnostic yield than CMA for fetuses with CNS abnormalities. Additionally, diagnostic rates for variants varied across different phenotypic abnormalities.\u003c/p\u003e","manuscriptTitle":"Prenatal Exome Sequencing of Fetuses with Central Nervous System Anomalies Based on Prenatal Ultrasound and Magnetic Resonance Imaging Diagnosis — A Retrospective Cohort Study and System Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-18 16:35:45","doi":"10.21203/rs.3.rs-5459992/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"107893605798826163900873715141835391324","date":"2025-03-19T11:58:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"69008187466112544545899422298899815169","date":"2025-03-12T10:30:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-21T03:59:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-11-18T14:20:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-16T08:38:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-16T08:38:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2024-11-15T10:59:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"686ef88b-25d0-4d74-8114-bd4bb401831f","owner":[],"postedDate":"December 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-12-18T16:35:45+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-18 16:35:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5459992","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5459992","identity":"rs-5459992","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}